Preclinical evaluation of dalbergin loaded PLGA-galactose-modified nanoparticles against hepatocellular carcinoma via inhibition of the AKT/NF-κB signaling pathway

• Published in: International immunopharmacology Vol. 140; p. 112813
• Main Authors: Gautam, Anurag Kumar, Kumar, Pranesh, Kumar, Vipin, Singh, Amita, Mahata, Tarun, Maity, Biswanath, Yadav, Sachin, Kumar, Dinesh, Singh, Sanjay, Saha, Sudipta, Vijayakumar, M.R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.10.2024
• Subjects: 1H NMR based metabolomics; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Dalbergin; Diethylnitrosamine; Galactose; Galactosylated nanoparticles; Hepatocellular carcinoma; Humans; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Male; Nanoparticles - chemistry; NF-kappa B - metabolism; PLGA nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Signal Transduction - drug effects; Targeted nanoparticles; CCSEA; DLMF; EDA; ALP; EDC; Targeted nanoparticles; DL; Hepatocellular carcinoma; ALT; K; 1H NMR based metabolomics; AUC; HDL; LDH; PDI; LDL; VLDL; CMC; CPMG; STAT-3; GSH; HPLC; WHO; CC; BCA; AST; 1H NMR; HCC; SOD; dN; TBARS; Dalbergin; DEN; ASGPR; PVDF; TA; PCA; TC; RC; PC; TG; Galactosylated nanoparticles; NC; CAT; BAX; PLGA nanoparticles; DLF; ELISA; H NMR based metabolomics
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112813

[Display omitted] •DL exhibits varying levels of cytotoxicity against the tumour and nearby normal cells.•The dalbergin nanoformulation (DLF) showed potential anticancer activity against diethyl nitrosamine (DEN) induced HCC in albino Wistar rats.•The dalbergin-loaded PLGA–galactose decorated nanoparticles (DLMF) resulted in significant anticancer activity against DEN-induced HCC in albino Wistar rats.•Immunoblotting studies revealed a reduction in the expression of many apoptotic markers, such as p53, BAX, and Cyt-C, in the HCC group.•After the treatment with DL, DLF, and DLMF all apoptotic markers, such as p53, BAX, Cyt-C and Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3 were normalized. Prior research has shown the effectiveness of dalbergin (DL), dalbergin nanoformulation (DLF), and dalbergin-loaded PLGA–galactose-modified nanoparticles (DLMF) in treating hepatocellular carcinoma (HCC) cells. The present investigation constructs upon our previous research and delves into the molecular mechanisms contributing to the anticancer effects of DLF and DLMF. This study examined the anti-cancer effects of DL, DLF, and DLMF by diethyl nitrosamine (DEN)-induced HCC model in albino Wistar rats. In addition, we performed biochemical, antioxidant, lipid profile tests, and histological studies of liver tissue. The anticancer efficacy of DLMF is equivalent to that of 5-fluorouracil, a commercially available therapy for HCC. Immunoblotting studies revealed a reduction in the expression of many apoptotic markers, such as p53, BAX, and Cyt-C, in HCC. Conversely, the expression of Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3 was elevated. Nevertheless, the administration of DL, DLF, and DLMF effectively controlled the levels of these apoptotic markers, resulting in a considerable decrease in the expression of Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3. Specifically, the activation of TNF-alpha and STAT-3 triggers the signalling pathways that include the Bcl-2 family of proteins, Cyt-C, caspase 3, and 9. This ultimately leads to apoptosis and the suppression of cell growth. Furthermore, metabolomic analysis using 1H NMR indicated that the metabolites of animals reverted to normal levels after the treatment.